EAL

CI: Supplemental Enteral Glutamine (2010)

Citation:

Houdijk AP, Rijnsburger ER, Jansen J, Wesdorp RI, Weiss JK, McCamish MA, Teerlink T, Meuwissen SG, Haarman HJ, Thijs LG, van Leeuwen PA. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet. 1998 Sep 5; 352(9,130): 772-776.

PubMed ID: 9737282

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To determine the effect of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple traumas.

Inclusion Criteria:

Each patient with multiple trauma admitted to the Academic Hospital of the Vrije Universiteit in Amsterdam was assessed by the Injury Severity Score, the Acute Physiology and Chronic Evaluation (APACHE) II score and the Glasgow Coma Scale.

Eligible patients:

Were between 18 to 65 years
Had an expected survival of more than 48 hours
Had an Injury Severity Score of 20 or more.

Exclusion Criteria:

Pregnancy or lactation
Renal insufficiency (serum creatinine 265mmol per L) at admission
Third degree burns involving more than 15% of body surface
Use of other investigational drugs, steroids or immunosuppressive medications
Malignancy
Genetic immune disorder
HIV infection
Previous splenectomy
Inflammatory bowel disease.

Description of Study Protocol:

Recruitment

Each patient with multiple trauma admitted to the Academic Hospital of the Vrije Universiteit in Amsterdam between January 1992 and January 1996 was assessed for inclusion.

Design

Randomized controlled trial
Subjects that met inclusion criteria were randomly allocated glutamine-supplemented enteral nutrition or a balanced, isonitrogenous, isocaloric enteral-feeding regimen. along with usual care.

Blinding Used

For identification of pneumonia, a radiologist who was unaware of treatment allocation reviewed all chest radiographs for new or changing infiltrates
To prevent interference with usual treatment, the protocol decisions about infections were not communicated to the attending intensivist or surgeon.

Intervention

Control (isocaloric, isonitrogenous per liter): 1,000kcal, 52g protein, 165g carbohydrate and 15g fat. 3.5g glutamine per 100g protein, which was made isonitrogenous with the glutamine-enriched formula by the addition of alanine, aspartate, glycine, proline and serine (Alitra Q - Ross Laboratories)
Glutamine-enriched enteral nutrition (per liter): 1,000kcal, 52g protein, 165g carbohydrate, 15g fat and 30.5g glutamine per 100g protein (supplied by Ross Laboratories)
Both feedings contained 8.5 arginine per 100g protein and similar concentrations of other essential amino acids.

Statistical Analysis

The sample size was calculated to detect a decrease in overall infectious morbidity in the glutamine-supplemented group. For this study, the authors assumed a 43% infection rate in the control group and a 12% incidence in the glutamine group, a sample size of 64 was needed with 80% power and 5% significance.
Differences in the proportions of infections between groups were analyzed by means of the x² test or Fisher's exact test where appropriate
According to protocol, the proportion of infections were analyzed only in patients who received enteral nutrition for a minimum of five days; patients fed for less than five days were not excluded from data collection and evaluation
An intention-to-treat analysis was done in which the data from all patients was included
Laboratory data were analyzed by means of ANOVA for repeated measures; if a significant overall difference between the groups was found, differences at several time points were analyzed by means of the Student's T-test
Length of stay in hospital was analyzed by the Mann-Whitney U test. Analyses were done with Stat-View (v 1.03).

Data Collection Summary:

Timing of Measurements

Patients were monitored for clinical signs of infection daily at eight-hour intervals
The concentrations of glutamine and arginine were measured on days one to five, seven and 14. Blood samples were taken between 8: A.M. and 10:00 A.M.

Dependent Variables

Infectious morbidity during the first 15 days was defined as:
- Sepsis/infection/pneumonia: Change in infiltrate on chest radiograph, and one of the following:
  - White blood-cell count greater than 12X10⁹ per L
  - Rectal temperature 38.3°C
  - Sputum gram stain with scores of more than two on a scale of four of polymorphonuclear leucocytes and bacteria
  - Growth of pathogenic organisms from sputum
- Sepsis: All of the following signs:
  - Clinical evidence of infection
  - Rectal temperature higher than 38.3°C
  - Heart rate higher than 90 beats per minute
  - Spontaneous respiratory rate higher than 20 breaths per minute.
  - At least one of the following:
    - Inadequate organ perfusion or organ dysfunction
    - Altered mentation since admission
    - Hypoxemia
    - Serum lactate more than the upper limit of the normal range (2.2mmol per L)
    - Oliguria with urine output lower than 30ml per hour or 0.5ml per kg^-1 per hour^-1, for at least one hour
- Bacteremia: One positive blood culture associated with a fever (rectal temperature higher than 38.3°C) or white blood-cell count greater than 12X10⁹per L
- Intrathoracic or intra-abdominal infection: One that required operative or percutaneous drainage
- Major wound infections: Those that involved deep fascia or deeper tissues
- Ventruculitis or meningitis: Positive cerebrospinal fluid culture not associated with an intracranial pressure monitor
- Positive culture of a central-line catheter and positive blood culture with resolution of fever after removal of the catheter
- Urinary tract infection: Isolation of at least 10⁵ colonies per ml of a pathogen from the urine
- Sinusitis: Rectal temperature of 38.3°C or higher and opacification of a sinus on radiography but without the need of operative treatment
Plasma concentrations of glutamine and arginine
Serum concentration of tumor necrosis factor
Days on mechanical ventilation
Length of stay.

Independent Variable

Glutamine-supplemented enteral nutrition.

Control Variable

Control and glutamine-supplemented enteral formulas were isocaloric and isonitrogenous.

Description of Actual Data Sample:

Initial N

80 (78% male)

Attrition (final N)

72 subjects:

Two were excluded from data analysis in control group (one died in less than 48 hours, one transferred)
Six were excluded from data analysis in glutamine group (two were more than 65 years old, two died died in less than 48 hours, one was found to have HIV, one transferred),

Age

Mean 35 years.

Other Relevant Demographics

Trauma patients:

Injury Severity Score: 32
APACHE II score: 16
Glasgow Coma Scale score: 8.5.

Location

Academic Hospital of the Vrije Unversiteit in Amsterdam.

Summary of Results:

Variable	Glutamine N=29	Control N=31	P-Value
Pneumonia (percentage)	5/29 (17%)	14/31 (45%)	0.02
Bacteremia (percentage)	2/29 (7%)	13/31 (42%)	0.005
Sepsis (percentage)	1/29 (3%)	8/31 (26%)	0.02
Days on mechanical ventilation (median and IQR)	7.6 (3.8 to 17.3)	9.0 (6.3 to 18.8)	0.50
Length of stay in hospital (median and IQR)	32.0 (23.8 to 35.8)	27.4 (17.3 to 34.5)	0.49

IQR=interquartile range

Other Key Findings

Feeding volume were similar between groups and NS difference in number of days on EN
Plasma concentrations of glutamine and arginine were significantly higher in treatment than control group
Serum concentration of tumor necrosis factor were significantly higher in control group than in glutaine group and peaked at day seven.

Author Conclusion:

There was a low frequency of pneumonia, sepsis and bacteraemia in patients with multiple trauma who received glutamine-supplemented enteral nutrition.

Funding Source:

Industry:

Ross Laboratories provided the products used in the study

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
	4.	Was method of handling withdrawals described?	Yes
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	Yes
	5.	Was blinding used to prevent introduction of bias?	Yes
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?	Yes
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
	7.	Were outcomes clearly defined and the measurements valid and reliable?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
	9.	Are conclusions supported by results with biases and limitations taken into consideration?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	10.	Is bias due to study's funding or sponsorship unlikely?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes